Imprinted Cdkn1c genomic locus cell-autonomously promotes cell survival in cerebral cortex development

• Published in: Nature communications Vol. 11; no. 1; pp. 195 - 14
• Main Authors: Laukoter, Susanne, Beattie, Robert, Pauler, Florian M., Amberg, Nicole, Nakayama, Keiichi I., Hippenmeyer, Simon
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/2; 13/31; 13/51; 14/19; 45/23; 45/90; 45/91; 631/136/368/2430; 631/337/176/1968; 631/378/2583; 64/60; Animals; Autonomy; CDKN1C protein; Cell Survival; Cells (biology); Cerebral cortex; Cerebral Cortex - growth & development; Cerebral Cortex - metabolism; Cyclin-dependent kinase; Cyclin-Dependent Kinase Inhibitor p57 - genetics; Cyclin-Dependent Kinase Inhibitor p57 - metabolism; Cyclin-dependent kinases; Enzyme inhibitors; Female; Gene Expression Regulation, Developmental; Genomic imprinting; Genomics; Humanities and Social Sciences; Kinases; Loci; Male; Mice; Mice, Knockout; multidisciplinary; Neurogenesis - genetics; Neurogenesis - physiology; Neuronal-glial interactions; Neurons - classification; Neurons - metabolism; Phenotype; Phenotypes; Progenitor cells; Science; Science (multidisciplinary); Survival; Transcriptome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-14077-2

The cyclin-dependent kinase inhibitor p57 KIP2 is encoded by the imprinted Cdkn1c locus, exhibits maternal expression, and is essential for cerebral cortex development. How Cdkn1c regulates corticogenesis is however not clear. To this end we employ Mosaic Analysis with Double Markers (MADM) technology to genetically dissect Cdkn1c gene function in corticogenesis at single cell resolution. We find that the previously described growth-inhibitory Cdkn1c function is a non-cell-autonomous one, acting on the whole organism. In contrast we reveal a growth-promoting cell-autonomous Cdkn1c function which at the mechanistic level mediates radial glial progenitor cell and nascent projection neuron survival. Strikingly, the growth-promoting function of Cdkn1c is highly dosage sensitive but not subject to genomic imprinting. Collectively, our results suggest that the Cdkn1c locus regulates cortical development through distinct cell-autonomous and non-cell-autonomous mechanisms. More generally, our study highlights the importance to probe the relative contributions of cell intrinsic gene function and tissue-wide mechanisms to the overall phenotype. How the imprinted Cdkn1c locus regulates corticogenesis is unclear. Here, the authors dissect the level of cell-autonomy of imprinted Cdkn1c gene function in mouse corticogenesis and identify this as regulating radial glial progenitor cell and projection neuron survival.